Inhibition of type 4 phosphodiesterase (PDE) by xanthine derivatives, including methylxanthine, such as theophylline, usually increases intracellular formation of cyclic AMP in various smooth muscle cells. Among them, theophylline is tranditionaly a non-selective PDE (phosphodiesterase) inhibitor (Beavo et al. Physiol Rev., 75, 725–748, 1995).
KMUP-1, a theophylline-based derivative, has been described to have not only minimum PDE (phosphodiesterase) inhibition but also enhanced cyclic GMP (guanosine 3′,5′-cyclic monophosphate) increasing activities in previous report (WU, B. N. et al. Br. J. Pharmacol., 134, 265–274, 2001). Type 5 PDE (phosphodiesterase) inhibitor such as sildanafil, with cyclic GMP (guanosine 3′,5′-cyclic monophosphate) increasing activity, has proved to be effective in the treatment of penile dysfunction after its oral administration in man (Goldstein I. et al. N. Engl. J. Med., 338, 1397–1404, 1998). However, KMUP-1, with minimum PDE (phosphodiesterase) inhibition as YC-1 but also with NO-releasing, and NO-independent sGC activation activity, similar to YC-!, to increase cyclic GMP activities in rat aortic smooth muscle, was thus supposed similarly to have rabbit cavernosal smooth muscle relaxation and penile erection effects in this invention.
Activation of soluble guanyl cyclase (sGC) induces the formation of cyclic GMP (guanosine 3′,5′-cyclic monophosphate), which is a second messenger of NO action, generally modulates the activity of its effector proteins that lead to vasorelaxation (Schmidt T. et al. Biochim. Biophys. Acta., 1178, 153–175, 1993) and also the opening of K+-channel (Murphy M. E. and Brayden, J. E. J. Physiol., 489, 723–734, 1995). It is reasonable to suggest that activation of sGC (soluble guanylyl cyclase) and inhibition of phosphodiesterase (PDE) that metabolize the cyclic GMP (guanosine 3′,5′-cyclic monophosphate), may together attribute to the increase of cyclic GMP associated vascular and cavernosal smooth muscle relaxations. YC-1 is a representative of this class of NO (nitric oxide)-independent sGC activator with PDE inhibition and may lead to a long-lasting cyclic GMP-mediated inhibition of vasoconstriction (Wu C. C. et al. Br. J. Pharmacol., 116, 1973–1978, 1995; Galle J. et al., Br. J. Pharmacol., 127, 195–203, 1999). Recently, BAY 41-2272 and BAY 51-9491 potently activate sGC (soluble guanylyl cyclase) by a mechanism that is also NO-independently (Stasch et al. Nature., 410, 212–215, 2001). KMUP-1 is thus suggested to have YC-1 like activity but having different chemical structure, characteristicly with theophylline base.